Drug combination therapy

ABSTRACT

The instant invention provides a drug combination comprised of an HMG-CoA reductase inhibitor in combination with an ACAT inhibitor, which is useful for treating or preventing Alzheimer&#39;s disease.

FIELD OF THE INVENTION

The instant invention involves a drug combination comprising a3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor incombination with a compound which inhibits acyl-coenzyme A:cholesterolacyltransferase (ACAT) for the treatment and prevention of Alzheimer'sdisease.

BACKGROUND OF THE INVENTION

Alzheimer's disease is a neurodegenerative disease of the brain leadingto severely impaired cognition and functionality. This disease leads toprogressive regression of memory and learned functions. Alzheimer'sdisease is a complex disease that affects cholinergic neurons, as wellas serotonergic, noradrenergic and other central neurotransmittersystems. Manifestations of Alzheimer's disease extend beyond memory lossand include personality changes, neuromuscular changes, seizures, andoccasionally psychotic features. Effective treatments for thisdevastating disease are not currently available.

One of the pathogenic events that occurs in identified inherited formsof Alzheimer's disease (AD) is the abnormal accumulation of amyloidβ-peptide (Aβ). Aβ is produced during normal cellular processing of theAlzheimer amyloid precursor protein (APP) by β- and γ-secretase (HaassC, et al., Amyloid beta-peptide is produced by cultured cells duringnormal metabolism, Nature 359:322-5, 1992). Although Aβ40 is the majorisoform of all the Aβ isoforms produced, about 10% of total Aβ consistsof the two-amino acid longer form, Aβ42. Accumulating evidence indicatesthat an increase in the Aβ42/Aβ total ratio accelerates the aggregationand accumulation of Aβ into amyloid fibrils, leading toneurodegeneration and synaptic loss (Selkoe D J, Translating cellbiology into therapeutic advances in Alzheimer's disease, Nature399:A23-31, 1999; Tanzi E R, A genetic dichotomy model for theinheritance of Alzheimer's disease and common age-related disorders, JClin Invest 104:1175-9, 1999). The molecular mechanisms that regulateAPP processing and Aβ generation are still largely unknown.

HMG-CoA reductase is the rate-limiting enzyme for the synthesis ofcholesterol. Inhibitors of HMG-CoA reductase, also known as stating,including marketed drugs such as lovastatin (MEVACOR®), simvastatin(ZOCOR®), pravastatin (PRAVACHOL®), fluvastatin (LESCOL®), andatorvastatin (LIPITOR®) lower plasma cholesterol and particularly lowdensity lipoprotein (IDL) cholesterol.

Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes thetransfer of a fatty acid to the hydroxyl group of cholesterol thattherefore becomes an ester. Since cholesterol esters are a key componentof the atherosclerotic plaque and since cholesterol esterification maycontribute to regulate cholesterol absorption, ACAT inhibitors have beensought as drug development candidates by a large number ofpharmaceutical companies for the treatment of lipid disorders andatherosclerosis.

Epidemiological studies have suggested a relationship between serumcholesterol levels and AD. Recently, two independent reports showed astrong decrease in the incidence of AD for patients that were treatedwith inhibitors of HMG-CoA reductase (Wolozin B, et al., Decreasedprevalence of Alzheimer disease associated with3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors, Arch Neurol57:143943, 2000; Jick H et al., Statins and the risk of dementia, Lancet356:1627-31, 2000). Results from Fassbender et al. (Fassbender K et al.,Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloidpeptides Abeta 42 and Abeta 40 in vitro and in vivo, Proc Natl Acad SciUSA. 98:5856-61, 2001) suggest that the beneficial effect from statinswith respect to AD may derive from their inhibitory effect on thegeneration of AP. It was found that treatment with statins reduces Aβ42in vitro and in vivo. More recently, studies from Puglielli et. al.(Puglielli L et al., Acyl-coenzyme A: cholesterol acyltransferasemodulates the generation of the amyloid β-peptide, Nature Cell Biology3:903-912,2001) showed that treatment with an ACAT inhibitor alsoreduces Aβ generation. Epidemiological studies have also indicated thatinflammation can be a factor leading to the progression of Alzheimer'sdisease.

This invention provides a method for preventing or reducing Aβformation, as well as reducing a patient's Aβ level. It also provides apharmaceutical drug combination therapy comprised of an ACAT inhibitorin combination with an HMG-CoA reductase inhibitor for treating,preventing or reducing the risk for onset of Alzheimer's disease.

SUMMARY OF THE INVENTION

This invention provides a pharmaceutical drug combination therapycomprised of a therapeutically or prophylactically effective amount ofan HMG-CoA reductase inhibitor in combination with a therapeutically orprophylactically effective amount of an ACAT inhibitor.

The drug combination can be used in methods for preventing or reducingthe risk for onset of Alzheimer's disease comprising administering aprophylactically effective amount of an HMG-CoA reductase inhibitor incombination with a prophylactically effective amount of an ACATinhibitor to patient in need thereof.

The drug combination can also be used in methods for treating or slowingthe progression of Alzheimer's disease comprising administering atherapeutically effective amount of an HMG-CoA reductase inhibitor incombination with a therapeutically effective amount of an ACAT inhibitorto patient in need thereof.

The drug combination can further be used in methods for preventing Aβformation comprising administering a prophylactically effective amountof an HMG-CoA reductase inhibitor in combination with a prophylacticallyeffective amount of an ACAT inhibitor to patient in need thereof.

The drug combination can also be used in methods for reducing Aβformation, as well as for reducing a patient's Aβ level, comprisingadministering a therapeutically effective amount of an HMG-CoA reductaseinhibitor in combination with a therapeutically effective amount of anACAT inhibitor to patient in need thereof.

Additional objects of this invention will be evident from the followingdetailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method for treating, preventing orreducing the risk for onset of Alzheimer's disease in a patientcomprising administering to said patient an HMG-COA reductase inhibitorin combination with a ACAT inhibitor in amounts that are effective totreat or prevent Alzheimer's disease.

A compound that inhibits HMG-CoA reductase is used in combination withan ACAT inhibitor to practice the instant invention. Compounds that haveinhibitory activity for HMG-CoA reductase can be readily identifiedusing assays well known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33, herein incorporated by reference.

Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. No. 4,231,938),simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784), pravastatin(PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin (LESCOL®; seeU.S. Pat. No. 5,354,772), atorvastatin (LIPITOR®; see U.S. Pat. No.5,273,995), pitavastatin (also known as NK-104, see U.S. Pat. Nos.5,284,953, 5,356,896 and 5,856,336), and rosuvastatin (also known asZD-4522, see U.S. Pat. No. 5,260,440). The hemi-calcium salt of NK-104is described and claimed in U.S. Pat. No. 5,856,336, and ZD-4522 isdescribed in Drugs of the Future, 1999, 24(5), pp. 511-513, while thestructural formulas of the other noted HMG-CoA reductase inhibitors, aswell as additional examples of HMG-CoA reductase inhibitors, aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (5 Feb. 1996). In general, HMG-CoAreductase inhibitors belong to a structural class of compounds whichcontain a moiety which can exist as either a 3-hydroxy lactone ring oras the corresponding 3,5-dihydroxy open-acid, and are commonly referredto as “statins.” The lactone portion of the statin and its correspondingdihydroxy open-acid form is shown below.

The term HMG-CoA reductase inhibitor is intended to include all lactoneand open-ring 3,5-dihydroxy open-acid forms of HMG-CoA reductaseinhibitors and the pharmaceutically acceptable salts and esters thereof;and therefor the use of such lactone and open-ring 3,5-dihydroxy acidforms and salts and esters thereof are included within the scope of thisinvention. Preferably, the HMG-CoA CoA reductase inhibitor is selectedfrom lovastatin and simvastatin, which are lactonized statins, and theircorresponding dihydroxy open acid forms and the pharmaceuticallyacceptable salts and esters thereof, and most preferably it is selectedfrom simvastatin and its dihydroxy open acid form and thepharmaceutically acceptable salts and esters thereof, including forexample the calcium and ammonium salts thereof.

Herein, the term “pharmaceutically acceptable salts” shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenzimidazole, diethylamine,piperazine, morpholine, 2,4,4-trimethyl-2-pentamine andtris(hydroxymethyl)-aminomethane. Pharmaceutically acceptable esters atthe carboxylic acid group can be made by treating a dihydroxy open acidstatin with an alcohol. Examples of pharmaceutically acceptable estersof dihydroxy open acid statins include, but are not limited to, —C₁₋₄alkyl and —C₁₋₄ alkyl substituted with phenyl-, dimethylamino-, andacetylamino. “C₁₋₄ alkyl” herein includes straight or branched aliphaticchains containing from 1 to 4 carbon atoms, for example methyl, ethyl,n-propyl, n-butyl, iso-propyl, sec-butyl and tert-butyl. Esterderivatives of the described compounds may act as prodrugs which, whenabsorbed into the bloodstream of a warm-blooded animal, may cleave insuch a manner as to release the drug form and permit the drug to affordimproved therapeutic efficacy.

A compound that inhibits ACAT is used in combination with an HMG-CoAreductase inhibitor to practice the instant invention. Recent work hasdemonstrated the existence of two distinct ACAT genes commonly referredto as ACAT-1 (sometimes referred to as ACAT I), described in U.S. Pat.No. 5,834,283, issued Nov. 10, 1998, and ACAT-2 (sometimes referred toas ACAT II), described in WO 97/45439 published Dec. 4, 1997. Compoundswhich have inhibitory activity for ACAT can be readily identified byusing assays well-known in the art, for example as described in Chang C.C., Lee C. Y., Chang, E. T., Cruz, J. C., Levesque, M. C., Chang, T. Y.:J. Biol. Chem.;273: 35132-35141, 1998: Recombinant acyl-CoA:cholesterolacyltransferase-1 (ACAT-1) purified to essential homogeneity utilizescholesterol in mixed micelles or in vesicles in a highly cooperativemanner, herein incorporated by reference. As used herein, compoundswhich inhibit either or both of the isoforms of ACAT are included withinthe meaning of the term “ACAT inhibitor” (as well as within the meaningof similar phrases such as an “inhibitor of ACAT”, “a compound thatinhibits ACAT” or the like) and are therefor within the scope of thisinvention. For example compounds which selectively or preferentiallyinhibit either ACAT-1 or ACAT-2, as well as compounds which have dualinhibitory activity for both ACAT-1 and ACAT-2, are useful with thepresent combination. Pharmaceutically acceptable salts and esters ofACAT inhibitors are likewise included within the scope of thisinvention.

Compounds which are ACAT inhibitors include but are not limited to thosedescribed in (i) U.S. Pat. No. 5,120,738 assigned to Fujirebio, Inc.;(ii) U.S. Pat. No. 5,340,807 assigned to Kyowa Hakkpo, Kogyo Co., Ltd.;(iii) U.S. Pat. No. 5,475,130 assigned to Taisho Pharmaceutical Co.,Ltd.; (iv) U.S. Pat. No. 5,668,136 assigned to Eisai Co., Ltd.; (v) U.S.Pat. No. 5,760,087 assigned to Pierre Fabre Medicament; (vi) WO96/26925applied for by Banyu Pharmaceutical Co., Ltd.; (vii) Sliskovic, D. R.,CI-1011: An atypical ACAT inhibitor with antiatherosclerotic activity,Proceedings, XIVth International Symposium on Medicinal Chemistry, F.Awouters (editor) Elsevier Science B. V., 433-441, 1997 and WO97/16184applied for by Warner-Lambert Co.; (viii) EP 0 635 501 A1 (EuropeanApplication No. 94305305.8); and (ix) Tanaka, A. et al., Inhibition ofacyl-CoA:cholesterol O-acyltransferase. 2. Identification andstructure-activity relationship of a novel series ofN-alkyl-N-(heteroaryl-substituted benzyl)-N′-arylureas, J. Med. Chem.,41:2390-2410, 1998, all of which are herein incorporated by reference.

Particular ACAT inhibitor compounds useful with this invention includeCompounds (i)-(ix) shown below and the pharmaceutically acceptable saltsand esters thereof:

which is described in U.S. Pat. No. 5,120,738;

which is described in U.S. Pat. No. 5,340,807;

which is described in U.S. Pat. No. 5,475,130;

which is described in U.S. Pat. No. 5,668,136;

which is described in U.S. Pat. No. 5,760,087;

which is described in WO96/26925;

which is described in the D. R. Sliskovic publication noted above,

described in EP 0 635 501 A1 and

described in the A. Tanaka et al., publication noted above.

The compounds of use in this invention may have one or more chiralcenters and the present compounds may occur as racemates, racemicmixtures and as individual diasteriomers or enantiomers with all suchisomeric forms and mixtures thereof being included within the scope ofthis invention. Furthermore, some of the crystalline forms for compoundsof the present invention may exist as polymorphs and as such areintended to be included in the present invention. In addition, some ofthe compounds of the instant invention may form solvates with water orcommon organic solvents. Such solvates and hydrates, as well asanhydrous compositions, are encompassed within the scope of thisinvention. Some of the compounds described herein may contain olefinicdouble bonds, and unless specified otherwise, are meant to include bothE and Z geometric isomers.

The ACAT inhibitors that may be used with this invention encompass allpharmaceutically acceptable salt forms of the compounds. Examples ofsuch salt forms of ACAT inhibitors include but are not limited to saltsderived from inorganic bases including aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

The instant pharmaceutical combination comprising an HMG-CoA reductaseinhibitor in combination with an ACAT inhibitor includes administrationof a single pharmaceutical dosage formulation which contains both theHMG-CoA reductase inhibitor and the ACAT inhibitor, as well asadministration of each active agent in its own separate pharmaceuticaldosage formulation. Where separate dosage formulations are used, theHMG-CoA reductase inhibitor and the ACAT inhibitor can be administeredat essentially the same time, i.e., concurrently, or at separatelystaggered times, i.e., sequentially. The instant pharmaceuticalcombination is understood to include all these regimens. Administrationin these various ways are suitable for the present invention as long asthe beneficial pharmaceutical effect of the HMG-CoA reductase inhibitorand the ACAT inhibitor are realized by the patient at substantially thesame time. Such beneficial effect is preferably achieved when the targetblood level concentrations of each active drug are maintained atsubstantially the same time. It is preferred that the HMG-CoA reductaseinhibitor and the ACAT inhibitor be co-administered concurrently on aonce-a-day dosing schedule; however, varying dosing schedules, such asthe HMG-CoA reductase inhibitor once per day and the ACAT inhibitoronce, twice or more times per day, is also encompassed herein. A singleoral dosage formulation comprised of both an HMG-CoA reductase inhibitorand the ACAT inhibitor is preferred.

The term “patient” is intended herein to mean human patients who take anHMG-CoA reductase inhibitor in combination with an ACAT inhibitor forany of the uses described herein. Administering of the drug combinationto the patient includes both self-administration and administration tothe patient by another person.

The term “therapeutically effective amount” is intended to mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, a system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.The term “prophylactically effective amount” is intended to mean thatamount of a pharmaceutical drug that will prevent or reduce the risk ofoccurrence of the biological or medical event that is sought to beprevented in a tissue, a system, animal or human by a researcher,veterinarian, medical doctor or other clinician. The present inventionencompasses not only treating a patient who displays symptoms ofAlzheimer's disease and reducing their level of Aβ, but also preventingthe onset or progression of the disease and the formation of Aβ.

The dosage regimen utilizing an HMG-CoA reductase inhibitor incombination with an ACAT inhibitor is selected in accordance with avariety of factors including type, species, age, weight, sex and medicalcondition of the patient; the severity of the condition to be treated;the route of administration; the renal and hepatic function of thepatient; and the particular compound or salt or ester thereof employed.Since two different active agents are being used together in acombination therapy, the potency of each of the agents and theinteractive effects achieved by combining them together must also betaken into account. A consideration of these factors is well within thepurview of the ordinarily skilled clinician for the purpose ofdetermining the therapeutically effective or prophylactically effectivedosage amounts needed to prevent, counter, or arrest the progress of thecondition.

The daily dosage amounts of the HMG-CoA reductase inhibitor are intendedto be the same or similar to those amounts which are employed foranti-hypercholesterolemic treatment and which are described in thePhysicians' Desk Reference (PDR). For example, see the 56^(th) Ed. ofthe PDR, 2002 (Medical Economics Co.); in particular, see at page 208the heading “Cardiovascular Agents,” sub-heading “Antilipemic Agents,”sub-sub-heading “HMG-CoA Reductase Inhibitors,” and the reference pagescited therein. For example, the oral dosage amount of HMG-CoA reductaseinhibitor can be from about 0.1 to 200 mg/day, or from about 1 to 200mg/day, preferably from about 0.1 to 100 mg/day, and more preferablyfrom about 5 to 80 mg/day. However, dosage amounts will vary dependingon the potency of the specific HMG-CoA reductase inhibitor used as wellas other factors as noted above. An HMG-CoA reductase inhibitor whichhas sufficiently greater potency may be given in sub-milligram dailydosages. The HMG-CoA reductase inhibitor may be administered from 1 to 4times per day, and preferably once per day.

As examples, the daily dosage amount for simvastatin may be selectedfrom 5 mg, 10 mg, 20 mg, 40 mg and 80 mg; for lovastatin, 10 mg, 20 mg,40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; forpravastatin sodium, 10 mg, 20 mg, and 40 mg; and for atorvastatincalcium, 10 mg, 20 mg, and 40 mg.

The ACAT inhibitor can be administered to a patient in a dosage amountof 50 mg or less per day, for example from about 0.1 to 50 mg per day,particularly from 0.1 to 40 mg per day, more particularly from 0.1 to 30mg per day, and most particularly from 0.1 to 20 mg per day. Examples ofdaily dosage amounts include but are not limited to 0.1, 1, 5, 10, 15,20, 25, 30, 35, 40, 45 and 50 mg per day.

The instant combination therapy can be administered chronically in orderto control the patient's Alzheimer's disease, and in order to gain thelong-term benefits of Alzheimer's disease treatment and prevention. Thedrug combination can also be administered acutely when warranted.

Additional active agents may be used in combination with the HMG-CoAreductase inhibitor and ACAT inhibitor in a single dosage formulation,or may be administered to the patient in a separate dosage formulation,which allows for concurrent or sequential administration. One or moreadditional active agents may be administered with the instantcombination therapy. The additional active agent or agents can be thoseuseful for the treatment of neurodegenerative disorders and/or haveother pharmaceutical activities. Examples of additional active agentswhich may be employed include HMG-CoA synthase inhibitors; squaleneepoxidase inhibitors; squalene synthetase inhibitors (also known assqualene synthase inhibitors), probucol; niacin; fibrates such asclofibrate, fenofibrate, and gemfibrizol; a cholesterol absorptioninhibitor such as ezetimibe which is1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,described in U.S. Pat. Nos. 5,767,115 and 5,846,966; bile acidsequestrants; LDL (low density lipoprotein) receptor inducers; plateletaggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogenreceptor antagonists and aspirin; vitamin B₆ (also known as pyridoxine)and the pharmaceutically acceptable salts thereof such as the HCl salt;vitamin B₁₂ (also known as cyanocobalamin); beta-blockers; folic acid ora pharmaceutically acceptable salt or ester thereof such as the sodiumsalt and the methylglucamine salt; and anti-oxidant vitamins such asvitamin C and E and beta carotene.

Examples of HMG-CoA synthase inhibitors include: the beta-lactonederivatives disclosed in U.S. Pat. Nos. 4,806,564, 4,816,477, 4,847,271,and 4,751,237; the beta lactam derivatives disclosed in U.S. Pat. No.4,983,597 and the substituted oxacyclopropane analogues disclosed inEuropean Patent Publication EP 0 411 703. The squalene synthetaseinhibitors suitable for use herein include, but are not limited to,those disclosed by Biller et al., J. Med. Chem., 1988 Vol. 31, No. 10,pp. 1869-1871, including isoprenoid (phosphinylmethyl)-phosphonates suchas those of the formula

including the triacids thereof, triesters thereof and tripotassium andtrisodium salts thereof as well as other squalene synthetase inhibitorsdisclosed in pending U.S. Pat. Nos. 4,871,721 and 4,924,024 and inBiller et al., J. Med. Chem., 1988, Vol. 31, No. 10, pp. 1869 to 1871.

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al., J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc. 1976, 98, 1291-1293,phosphinylphosphonate reported by McClard, R. W. et al., J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U. of Utah, Abstract, Table of Contents,pp. 16, 17, 4043, 48-51, Summary.

Further, the benzodiazepine squalene synthase inhibitors described in EP0 567 026 to Takeda Chemical Industries, and the quinuclidinyl squalenesynthase inhibitors described in PCT publications WO 94/03451, WO93/09115, WO 93/21183, WO 93/21184, WO 93/24486, and U.S. Pat. No.5,135,935, may be co-administered with the HMG-CoA reductase inhibitorplus ACAT inhibitor combination of the present invention. In addition,the zaragozic acid type squalene synthase inhibitors as described inU.S. Pat. Nos. 5,284,758; 5,283,256; 5,262,435; 5,260,332; 5,264,593;5,260,215; 5,258,401; 5,254,727; 5,256,689; 5,132,320; 5,278,067, andPCT Publications WO 92/12156; WO 92/12157; WO 92/12158; WO 92/12159; WO92/12160; WO 93/18040; WO 93/18039; WO 93/07151; and European PatentPublications EP 0 512 865, EP 0 568 946; EP 0 524,677 and EP 0 450 812,as well as the acyclic tricarboxylic acid compounds of U.S. Pat. No.5,254,727, may be employed.

Illustrative examples of squalene epoxidase inhibitors are disclosed inEuropean Patent Publication EP 0 318 860 and in Japanese PatentPublication JO2 169-571A. LDL-receptor gene inducer molecules aredisclosed in U.S. Pat. No. 5,182,298.

Examples of bile acid sequestrants which may be employed in the presentmethod include cholestyramine, colestipol, and poly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide] and thosedisclosed in WO95/34585 to Geltex Pharmaceuticals, Inc. and EP 0 622 078assigned to Hisamitsu Pharmaceutical Co., Inc.

Examples of cholesterol absorption inhibitors which may be employed inthe present method include those described in WO 95/18143 and WO95/18144 both assigned to Pfizer Inc., and WO 94/17038, WO 95/08532 andWO 93/02048 each assigned to Schering Corp.

The additional active agents described above which may be employed alongwith the HMG-CoA reductase inhibitor and ACAT inhibitor combinationtherapy can be used, for example, in amounts as indicated in the PDR orin amounts as indicated in the reference disclosures, as appropriate.

The active agents employed in the instant combination therapy can beadministered in such oral forms as tablets, capsules, pills, powders,granules, elixirs, tinctures, suspensions, syrups, and emulsions. Theinstant invention includes the use of both oral rapid-release andtime-controlled release pharmaceutical formulations, as well as entericcoated formulations. A particular example of an oral time-controlledrelease pharmaceutical formulation is described in U.S. Pat. No.5,366,738. Oral formulations are preferred. Such pharmaceuticalcompositions are known to those of ordinary skill in the pharmaceuticalarts; for example, see Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa.

In the methods of the present invention, the active agents are typicallyadministered in admixture with suitable pharmaceutical diluents,excipients or carriers (collectively referred to herein as “carrier”materials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, elixirs, syrups and thelike, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with a non-toxic,pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, modified sugars, modified starches, methyl celluloseand its derivatives, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and other reducing and non-reducing sugars, magnesium stearate,steric acid, sodium stearyl fumarate, glyceryl behenate, calciumstearate and the like. For oral administration in liquid form, the drugcomponents can be combined with non-toxic, pharmaceutically acceptableinert carrier such as ethanol, glycerol, water and the like. Moreover,when desired or necessary, suitable binders, lubricants, disintegratingagents and coloring and flavoring agents can also be incorporated intothe mixture. Stabilizing agents such as antioxidants (BHA, BHT, propylgallate, sodium ascorbate, citric acid) can also be added to stabilizethe dosage forms. Other suitable components include gelatin, sweeteners,natural and synthetic gums such as acacia, tragacanth or alginates,carboxymethylcellulose, polyethylene glycol, waxes and the like.

The active drugs can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Active drug may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Activedrug may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinyl-pyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, active drug may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels.

Although the active agents of the present method may be administered individed doses, for example two or three times daily, a single daily doseof each of the HMG-CoA reductase inhibitor and the ACAT inhibitor ispreferred, with a single daily dose of both agents in a singlepharmaceutical composition being most preferred.

The instant invention also encompasses a process for preparing apharmaceutical composition comprising combining the BMG-CoA reductaseinhibitor and the ACAT inhibitor with a pharmaceutically acceptablecarrier, as well as the pharmaceutical composition which is made bycombining the HMG-CoA reductase inhibitor and the ACAT inhibitor with apharmaceutically acceptable carrier.

Therapeutically effective amounts of antihypertensive compound orcompounds and cholesterol absorption inhibitor can be used together forthe preparation of a medicament useful for treating or preventing any ofthe medical conditions described herein, in dosage amounts describedherein. For example, the medicament may be useful for treatinghypertension, preventing or reducing the risk of developingatherosclerotic disease, halting or slowing the progression ofatherosclerotic disease once it has become clinically manifest, andpreventing or reducing the risk of a first or subsequent occurrence ofan atherosclerotic disease event.

The instant invention also encompasses the use of a therapeutically orprophylactically effective amount, as appropriate, of an HMG-CoAreductase inhibitor for the preparation of a medicament for combined usewith a therapeutically or prophylactically effective amount, asappropriate, of an ACAT inhibitor. for preventing or reducing the riskfor onset of Alzheimer's disease, treating or slowing the progression ofAlzheimer's disease, preventing or reducing Aβ formation, as well as forreducing a patient's Aβ level.

The instant invention also encompasses the use of an effective amount ofan HMG-CoA reductase inhibitor and an effective amount of an ACATinhibitor for the preparation of a medicament useful for preventing orreducing the risk for onset of Alzheimer's disease, treating or slowingthe progression of Alzheimer's disease, preventing or reducing Aβformation, or for reducing a patient's Aβ level. The effective amount ofeach active agent is either a therapeutically or prophylacticallyeffective amount, as appropriate, depending on whether the medicamentcan be used in methods of treatment or prevention.

The instant invention also encompasses the use of a therapeutically orprophylactically effective amount, as appropriate, of an HMG-CoAreductase inhibitor for the preparation of a medicament for combined usewith a therapeutically or prophylactically effective amount, asappropriate, of an ACAT inhibitor, wherein the medicament is useful fortreatment or prevention of any of the conditions described herein. Theinstant invention further encompasses the use of a therapeutically orprophylactically effective amount, as appropriate, of an ACAT inhibitorfor the preparation of a medicament for combined use with atherapeutically or prophylactically effective amount, as appropriate, ofan HMG-CoA reductase inhibitor, wherein the medicament is useful fortreatment or prevention of any of the conditions described herein.

The medicament or pharmaceutical drug combination comprised of the anHMG-CoA reductase inhibitor and the ACAT inhibitor may also be preparedwith one or more additional active agents, such as those describedabove.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, specific effective dosage amounts other than theparticular dosages as set forth herein above may be applicable as aconsequence of variations in the responsiveness of the mammal beingtreated for any of the indications for the active agents used in theinstant invention as indicated above. Likewise, the specificpharmacological responses observed may vary according to and dependingupon the particular active compound selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A method for preventing Aβ formation comprising administering aprophylactically effective amount of an HMG-CoA reductase inhibitor incombination with a prophylactically effective amount of an ACATinhibitor to patient in need thereof.
 2. A method for reducing Aβformation comprising administering a therapeutically effective amount ofan HMG-CoA reductase inhibitor in combination with a therapeuticallyeffective amount of an ACAT inhibitor to patient in need thereof.
 3. Amethod for preventing or reducing the risk for onset of Alzheimer'sdisease comprising administering a prophylactically effective amount ofan HMG-CoA reductase inhibitor in combination with a prophylacticallyeffective amount of an ACAT inhibitor to patient in need thereof
 4. Amethod for treating Alzheimer's disease comprising administering atherapeutically effective amount of an HMG-CoA reductase inhibitor incombination with a therapeutically effective amount of an ACAT inhibitorto patient in need thereof.
 5. The method according to claim 4 whereinthe HMG-CoA reductase inhibitor is selected from the lactone anddihydroxy open-acid forms of lovastatin, simvastatin, pravastatin,fluvastatin, atorvastatin, rosuvastatin, pitavastatin and thepharmaceutically acceptable salts and esters thereof.
 6. The method ofclaim 5 wherein the HMG-CoA reductase inhibitor is selected from thelactone and dihydroxy open-acid forms of simvastatin and thepharmaceutically acceptable salts and esters thereof.
 7. The method ofclaim 5 wherein the HMG-CoA reductase inhibitor is selected from thelactone and dihydroxy open-acid forms of lovastatin and thepharmaceutically acceptable salts and esters thereof.
 8. The method ofclaim 4 wherein the ACAT inhibitor is selected from the group consistingof:

and the pharmaceutically acceptable salts and esters thereof.